Corrosion Behavior And Biocompatibility Of Ultrafine-grained Copper-magnesium Alloys In Uterine Cavity Microenvironment

Appropriate contraceptive methods,as important ways to protect the reproductive health of female,include long-acting copper-containing and drug-bearing intrauterine device(IUD)suitable for long-term contraception,and short-acting hormonal containing contraceptive devices such as dermal implants and vaginal rings which are suitable for months or 1-2 years of contraception.Copper-containing IUD with the characteristics of efficacy,safety and cost-effectiveness is a very popular method for birth control.However,the burst release of cupric ions in the initial stage and the deposition of corrosion products in the later stage are associated with several adverse effects of Cu IUD such as bleeding,pelvic pain and inflammation.These side effects account for the high rate of discontinuation of copper-containing IUDs among women.Short-acting contraceptive methods are mostly depending on hormones,which can gradually lead to too little menstrual flow and even amenorrhea resulting in the decreased use of hormone-based contraceptives.In order to reduce the side effects of IUD,ultra-fine grained copper(UFG Cu)had been explored by our previous study,and the burst release of cupric ion was effectively decreased.To further reduce the burst release of cupric ion and elevate the biocompatibility,we proposed a novel strategy by incorporating a limited percentage of bioactive magnesium into the copper matrix without changing the contraception efficacy,and the alloy was pressed through equal channel angular pressing(ECAP)to prepare the ultra-fine grained copper-magnesium alloy containing 0.4(wt.%)magnesium(UFG Cu-0.4Mg).Given the metallic activity of magnesium,the burst release of cupric ion would be inhibited by preferential corrosion of magnesium in the uterine fluid.Thus,the incidence of side effects of the existing IUD would be reduced and improve the utilization rate of IUD.Magnesium,as an essential element for human body,plays an important role in cells by binding to the enzymes and nucleic acids.Pure magnesium and magnesium-based alloys with the characteristics of biodegradability,good mechanical property,and mild inflammatory response have been widely designed into bone implants and cardiovascular intervention materials.Previous study directed by our group showed that magnesium and magnesium-based alloys are also suitable for being applied in intrauterine environment without cytotoxicity.Moreover,Mg2+ are also known as uterine relaxants in clinic and magnesium sulfate has been used in the management of severe pre-eclampsia.Magnesium ions also have the ability to inhibit the spontaneous contraction of uterine smooth muscle.If it was introduced into IUD,with the release of magnesium ions into the uterine cavity,the abnormal contraction of uterine smooth muscle would be relived.Therefore,pain,bleeding,and discharge which are related to the contraction of uterine smooth muscle will also be relived.However,the alloying magnesium should be limited in a certain proportion,above which it can adversely affect mechanical property of the IUD given the biodegradability of Mg in vivo.Thus,in the present work,UFG Cu-0.4%Mg alloy was proposed as a potential candidate of IUD.On the one hand,it could maintain good mechanical property and long-term performance.On the other hand,the burst release of copper ion would be reduced with the co-release of Cu2+and Mg2+ and increase the biocompatibility of IUD.Therefore,in vitro long-term immersion test,cytotoxicity experiments,and in situ implantation were performed to evaluate the corrosion characteristics,biocompatibility and contraceptive efficiency of UFG Cu-0.4Mg materials compared with UFG Cu and coarse grained copper(CG Cu)?The main findings are as follows:1.The in vitro immersion experiment revealed that with the release of magnesium ions,UFG Cu-0.4Mg showed significant lower release rate of copper ions in the early stage and kept a slightly higher release amount of copper ions than that in UFG Cu and CG Cu.The analysis of corrosion morphology showed that the corrosion process of the three groups of materials was ranked as UFG Cu-0.4Mg<UFG Cu<CG Cu,and the main corrosion product was Cu2O.Electrochemical experiments showed that the corrosion rate of UFG cu-0.4mg material was significantly lower than that of UFG Cu and CG Cu.2.The concentration of cupric ion in UFG Cu-0.4Mg extraction was significantly lower than that of UFG Cu and CG Cu,while the concentration of magnesium ion increased slightly.The cytotoxicity of 100%and 50%extraction on endometrial epithelial cells,endometrial stromal cells,human umbilical vein endothelial cells and L929 cells was high.The cytocompatibility of 10%UFG Cu-0.4Mg extraction was significantly higher than that of the other two groups without inducing the expression of inflammatory related factors in human endometrial stromal cells.3.In vivo implantation experiments showed that a significant decline in cupric ions release and improvement in histocompatibility of UFG Cu-0.4Mg were found with the addition of magnesium.4.After implantation,the three group showed different corrosion morphologies:CG Cu material was covered by uniform pieces which peeled off in the later stage,exposing the copper matrix;the corrosion surface of UFG Cu was similar to that of CG Cu experiencing peeling off of corrosion products on the Cu2O corrosion layer;while the addition of magnesium significantly improved the corrosion performance of UFG Cu-0.4Mg,the corrosion products were compactly arranged pieces uniformly distributed on the surface.Cu2O was the main corrosion product,and a small amount of CuS,CuO and Cu2S were also detected.5.The antifertility experiment showed that the contraceptive efficacy of UFG Cu-0.4Mg is as excellent as CG Cu and UFG Cu.In conclusion,the UFG Cu-0.4Mg alloy exhibited better corrosion behavior and biocompatibility in the intrauterine microenvironment.Therefore,these results suggested that UFG Cu-0.4Mg alloy would be a potential intrauterine device.At the same time,it also provided new perspective for the design of IUD.Meanwhile,the improvement of contraception method is of great significance in the field of reproductive health.